The vinyloxycarbonyl unit is a useful moiety for the N-protection of amino acids, and in the protection of phenols. However, its introduction via vinyl chloroformate suffers from the difficulty in preparing pure vinyl chloroformate from either the gas phase decomposition of ethylene glycol bis(chloroformate) or by acylation of ketone enolates with phosgene. The present invention is directed to the synthesis of vinyl phenylthiocarbonate, hereinafter also referred to as VOC-SPh, and to the use of VOC-SPh for the introduction of the vinyloxycarbonyl protective group, hereinafter also referred to as VOC, into amino acids.
The lithium enolate of acetaldehyde (III) is formed by the action of n-butyllithium (II) on tetrahydrofuran (I) with ethylene and butane generated as by-products according to the following scheme: ##STR1##
According to the present invention, acylation with phenyl thiochloroformate (IV) affords vinyl phenylthiocarbonate (V) in 65% isolated yield according to the following scheme: ##STR2##
In contrast to vinyl chloroformate, vinyl phenylthiocarbonate is very stable towards light and ambient temperatures with no decomposition observed by NMR after one week in deuterochloroform solution. Although the reagent is stable to aqueous base, it reacts readily with amino acids at about pH 9.5 to generate the vinyl urethane, i.e., vinyloxycarbonyl amino acid, hereinafter also referred to as VOC-AA, and thiophenol according to the following scheme: ##STR3## wherein R is the amino acid side chain.
The reaction proceeds most efficiently in solvent systems, such as dioxane-water or DMF-water, which afford the proper polarity for concurrent solubility of the VOC-SPh and the amino acid and weak bases such as triethylamine.
The following Examples are given for the purpose of illustration and not by way of limitation.